Answering the Call in Severe Asthma

Educational Objectives

• Describe key pathophysiologic processes in severe asthma development and persistence, including the roles of TSLP and implications for treatment

• Discuss the clinical profiles and recent trial results with newer biologic therapies for severe asthma

• Construct biologic-based treatment regimens for patients with severe asthma to maximize asthma control, prevent exacerbations, and incorporate shared clinical decision making

TSLP, thymic stromal lymphopoietin.

UNDERLYING MECHANISMS IN SEVERE ASTHMA

Michael E. Wechsler, MD, MMSc

The Dynamic Airway Epithelium

The First Piece in the Sequence of Asthma Inflammation

vs

• Characteristics of the Asthma Airway:

– Inflammation

– Hyperreactivity

– Recurrent, reversible obstruction

• Contributing factors:

– Disruption of microbiome

–

Excessive goblet cell differentiation

– Excessive mucus production

–

–

Dysfunctional cilia movement

Epithelial Cytokine Networks in Asthma

A Closer Look at T2-High-Driven Disease

Allergens

Irritants, pollutants, microbes, and viruses

T2-high cytokines1,2

– IL-4, IL-5, & IL-13

– Produced by Th2 and ILC2 cells

Biomarkers1,2

–

Eosinophilia

–

Elevated IgE

–

Elevated FeNO

Atopic

Nonatopic

CRTH2, chemoattractant receptor-homologous molecule expressed on Th2 cells; DC, dendritic cell; DR3, death receptor 3; EC, endothelial cell; GATA3, GATA binding protein 3; GC, goblet cell; ILC2, innate lymphoid cell type 2; KIT, receptor tyrosine kinase; MHC, major histocompatibility complex; PGD2, prostaglandin D2; SM, smooth muscle; ST2, IL-33 receptor; T2, type 2; TCR, T cell receptor; TGR, transforming growth factor; Th, T-helper cell; TNF, tumor necrosis factor; TL1A, TNF-like protein 1A; TSLP, thymic stromal lymphopoietin. Image adapted from Corren J. J Allergy Clin Immunol Pract. 2019;7(5):1394-1403 and Israel

Mucus Plugging and Hypersecretion A Closer Look at T2-High-Driven Disease

Normal

Mucus hypersecretion

Asthma epithelium

Asthma GC ASM

• Substantial plugging in most patients with fatal asthma; persists in the same airways over time, increasing in frequency with disease severity1

• IL-13-mediated

– Proliferation of hypersecretory MUC5AC-expressing mucus cells2,3

– Loss of ciliated cells2

– Increase in thiocyanate transport3

Eosinophil-rich mucus plug

Eosinophil exotaxis

• Thiocyanate reacts with eosinophil peroxidase, promoting cross-linking of mucins, mucus gel stiffening, and resultant mucus plug formation

– Activation of

and release of granule proteins

Numerous studies, including case reports, post-hoc and meta-analysis, have explored the role of biologic therapies in the reduction of mucus plugging.

Epithelial Cytokine Networks in Asthma

A Closer Look at T2-Low Driven Disease

Alarmin-Mediated Inflammatory Pathways

• T2-low cytokines1-3

– IL-1β, IL-6, IL-8, IL-17, & TNF-α

– Produced by Th17 and Th1 cells

• No reliable biomarkers beyond absence of T2-high biomarkers

• Neutrophilic or paucigranulocytic

Epithelial Cytokine Networks in Asthma

A Closer Look at T2-Low Driven Disease

IL-6-Mediated Airway Inflammation

Homeostasis

Infection

Tight Junctions

Exacerbations

• T2-low cytokines1-3 – IL-1β, IL-6, IL-8, IL17, & TNF-α

– Produced by Th17 and Th1 cells

• No reliable biomarkers beyond absence of T2high biomarkers

• Neutrophilic or paucigranulocytic

MIP, macrophage inflammatory protein; MMP, matrix metalloproteinase; PAMP, pathogen-associated molecular pattern; TLR, toll-like receptor.

1. Kalchiem-Dekel O, et al. Chest. 2020;157(1):26-33; 2. Hinks TSC, et al. Eur Respir J. 2021;57(1):2000528; 3. Lambrecht BN, et al. Immunity. 2019;50(4):975-991.

Image adapted from Jevnikar Z, et al. J Allergy Clin Immunol. 2019;143(2):577-590.

Airway Smooth Muscle

The Final Common Pathway in Asthma

• ASM cells contribute to1

–

– Narrowing

–

– Remodeling

• ASM contraction releases mast cell mediators2

– Mast cell myositis is observed in various asthma phenotypes

• ASM may also drive mucus hypersecretion3

Targeting Underlying Mechanisms of Disease

6 FDA-Approved Biologics for Asthma

Agent Target Indication(s)

Omalizumab IgE

• Moderate-to-severe, persistent asthma inadequately controlled with ICS; (+) skin test or in vitro reactivity to aeroallergen; age ≥6 years

• Symptomatic CSU despite H1AH; age ≥12 years

• Nasal polyps with inadequate response to INCS; age ≥18 years

Reslizumab IL-5

• Severe asthma, eosinophilic phenotype; age ≥18 years

• Severe asthma, eosinophilic phenotype; age ≥6 years

Mepolizumab IL-5

• CRSwNP; age ≥18 years

• EGPA; age ≥18 years

• HES that lasts for ≥6 months without identifiable nonhematologic secondary cause; age ≥12 years

Benralizumab IL-5Rα

• Severe asthma, eosinophilic phenotype; age ≥12 years

• Moderate-to-severe asthma, eosinophilic phenotype OR OCS-dependent; age ≥6 years

Dupilumab IL-4Rα

• Inadequately controlled CRSwNP; age ≥18 years

• Moderate-to-severe atopic dermatitis inadequately controlled with topical therapy OR contraindication to topical therapy; age ≥6 years

Tezepelumab TSLP

• Severe asthma; age ≥12 years

H1AH, oral H1-antihistamine; CRSwNP, chronic rhinosinusitis with nasal polyps; CSU, chronic spontaneous urticaria; EGPA, eosinophilic granulomatosis with polyangiitis; FDA, US Food and Drug Administration; HES, hypereosinophilic syndrome; ICS, inhaled corticosteroids; IgE, immunoglobulin E; IL, interleukin; INCS, intranasal corticosteroids; OCS, oral corticosteroid; R, receptor; SA, severe asthma. Drugs @ FDA. https://www.accessdata.fda.gov/scripts/cder/daf/.

Biologic therapies have revolutionized the treatment of severe asthma by reducing asthma exacerbations as demonstrated in randomized placebo-controlled trials.

NEWER THERAPEUTIC TARGETS IN SEVERE ASTHMA Monica

Kraft, MD

Newer Therapeutic Targets in Asthma

Target Mechanism Agent Stage of Development

• Tezepelumab, anti-TSLP

• Ecleralimab, inhaled anti-TSLP

• Itepekimab, anti-IL-33

Alarmins

TSLP IL-33 IL-25

• Epithelial tissue damage → release of alarmins (epithelial cell-derived cytokines) → drives inflammatory responses by activating dendritic cells and mast cells

• Etokimab, anti-IL-33

• FDA Approved

• Phase 2a – Terminated in Asthma

• Phase 2 – Completed; Development Terminated in Asthma; Investigations in COPD Ongoing

• Phase 2a – Completed

• Phase 2b/3 – Ready; No Further Internal Investment

• Astegolimab, anti-ST2 (IL-33 receptor)

Mast cells

• IgE cross-linking → Mast cell degranulation → mediators including histamine, tryptase, chymase, carboxypeptidase Th1

• Obesity/granulocytes → IL-6 → steroid-resistant inflammation

IL-6

• IL-6 trans-signaling: bacteria → TLRs → granulocytes shed soluble IL-6R + IL-6 → local epithelial cell inflammations

• Masitinib, TKI

• Imatinib, TKI

• Tocilizumab, anti-IL-6R

• Sirukumab

• Phase 2b – Completed; Development Terminated in Asthma; Investigations in COPD Ongoing

• Phase 3 – Completed

• Phase 2 – Completed

• Off-label Case Studies

• Phase 2a – Withdrawn Prior to Participant Enrollment

COPD, chronic obstructive pulmonary disease. TKI, tyrosine kinase . Hinks TSC, et al. Eur Respir J. 2021;57(1):2000528; Wechsler ME. Respir Care. 2018;63(6):699-707; E, et al. . 2020;75(2):311325; Clinicaltrials.gov. https://clinicaltrials.gov/ct2/home. 6, 2023; Esty B, et al.

inhibitor

Kelson SG, et al. J Allergy Clin Immunol. 2021;148(3):790798;

Sze Allergy Accessed February J Allergy Clin Immunol Pract. 2019;7(5): 1639–1642.e4; Press release. https://ir.anaptysbio.com/news-releases/news-release-details/anaptysbio-presents-updated-data-etokimab-phase-2a-proof-concept. Accessed April 25, 2023.

Tezepelumab – Anti-TSLP

Pivotal Phase 3 Navigator Trial1

Annualized Rate of Exacerbations

• SAFETY – Serious AE

• Tezepelumab, 9.8%

• Placebo, 13.7%

• Reductions from baseline in blood

eosinophil counts and FeNO levels were also observed

aP<0.001 vs placebo. AE, adverse event; Q4W, every 4 weeks; RR, relative reduction; SQ, subcutaneous. N=1061 patients aged 12- 80 years with severe uncontrolled asthma requiring medium- or high-dose ICS (daily dose of ≥500 μg of fluticasone propionate or equivalent) plus ≥1 controller medication with/without OCS were randomized 1:1 to tezepelumab 210 mg SQ (n=529) or placebo (n=532) Q4W for 52 weeks. The primary endpoint was reduction in annualized exacerbation rates.

1. Menzies-Gow A, et al. N Engl J Med. 2021;384(19):1800-1809; 2. Pharmacy Times. https://www.pharmacytimes.com/view/fda-approves-pre-filled-pen-for-self-administration-of-tezepelumab-ekko-to-treat-asthma.

Accessed February 6, 2023; 3. European Pharmaceutical Review (EPR). https://www.europeanpharmaceuticalreview.com/news/178513/pre-filled-asthma-auto-injector-pen-approved-for-self-administration-in-eu/. Accessed January 23, 2023.

Other Tezepelumab Studies

Study Details Results

DESTINATION1

• Long-term extension study of tezepelumab in adults and adolescents with severe uncontrolled asthma who completed the NAVIGATOR or SOURCE studies (Phase 3)

• Sustained reductions in AAER over 104 weeks vs placebo of 58% (NAVIGATOR) and 39% (SOURCE); reduced biomarker levels vs placebo; overall long-term safety and efficacy consistent with the previous studies.

PASSAGE2

• Real-world effectiveness and safety study of tezepelumab in a broad population of adults and adolescents with severe asthma, including underrepresented patients in clinical trials (Phase 4)

WAYFINDER3

• Study to Evaluate Efficacy and Safety of Tezepelumab in Reducing Oral Corticosteroid Use in Adult Patients With Severe Asthma

(Phase 3)

• Ongoing

• Ongoing

AAER, annualized asthma exacerbation rate. 1. Menzies-Gow A, et al. DESTINATION: tezepelumab long-term safety and efficacy versus placebo in patients with severe, uncontrolled asthma. European Respiratory Society (ERS) International Congress 2022, Oral Presentation OA9002, https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.ers/abstract_2022/95944.html.pdf; 2. Lugogo N, et al. CHEST; 2022;162(4):A37A40. https://journal.chestnet.org/article/S0012-3692(22)01383-6/fulltext; 3. Clinicaltrials.gov. Study to Evaluate Efficacy and Safety of Tezepelumab in Reducing Oral Corticosteroid Use in Adult Patients With Severe Asthma (WAYFINDER). Available at https://clinicaltrials.gov/ct2/show/NCT05274815. Accessed January 23, 2023.

Itepekimab – Anti-IL-33 Phase

2 Study

Loss of Asthma Control Change in Eosinophil Count

Weeks Since Randomization

Weeks Since

While development of itepekimab has been discontinued in asthma, studies investigating its efficacy/safety in COPD are ongoing.

aOR=0.52 vs placebo; bOR=0.42 vs placebo; cOR=0.33 vs placebo; OR, odds ratio; Q2W, every 2 weeks. N=296 adult patients with moderate-to-severe asthma receiving inhaled glucocorticoids plus LABAs received (1:1:1:1) itepekimab 300 mg SQ (n=73), itepekimab plus dupilumab, both 300 mg SQ (n=74), dupilumab 300 mg SQ (n=74), o r placebo (n=74) Q2W for 12 weeks. LABA was discontinued at week 4 and inhaled glucocorticoids were tapered over weeks 6 through 9.

Wechsler ME, et al. N Engl J Med. 2021;385(18):1656-1668.

Etokimab – Anti-IL-33 Phase

2a Proof-of-Concept Study

While positive Phase 2a trial results were positive, further internal investigation has been discontinued.

IV, intravenously. N=25 adults with severe asthma, blood eosinophils ≥300 cells/µL, pre-bronchodilator FEV1 <80% of predicted, and ≥1 asthma exacerbation within the past 12 months requiring use of rescue medication were randomized to etokimab 300 mg IV or placebo. Press release. https://ir.anaptysbio.com/news-releases/news-release-details/anaptysbio-presents-updated-data-etokimab-phase-2a-proof-concept.

Accessed April 25, 2023.

Astegolimab – Anti-ST2

IL-33 Receptor Monoclonal Antibody─Phase 2b Study

While development of astegolimab has been discontinued in asthma, studies investigating its efficacy/safety in COPD are ongoing.

Phase 3 Study in OCS-dependent SA

Primary analysis; no minimum baseline blood eos

Masitinib reduced severe asthma exacerbations and demonstrated a positive benefit/risk ratio in patients with severe asthma uncontrolled by OCS, irrespective of baseline eosinophil count.

=0.01; bP=0.025. eos, eosinophils. N=355 adult patients (primary population) with severe persistent asthma uncontrolled by OCS (≥7.5 mg/day) and high-dose ICS/LABA were randomized 2:1 to oral masitinib (6 mg/kg/day) or placebo for 36 weeks. The primary endpoint was reduction of annualized asthma exacerbation rate adjusted for overall exposure. Davidescu L, et al. J Asthma Allergy. 2022;15:737-747.

Imatinib – TKI

Phase 2 Proof-of-Principle Study

Airway Hyperresponsiveness

Total Tryptase Levels in Serum

Imatinib increased the methacholine PC20 by a mean of 1.20 doubling doses from baseline to month 3 and by 1.73 doubling doses from baseline to month 6.

Evidence of mast cell activity was also reduced per decreased tryptase levels.

QD, once daily; PC20, concentration of methacholine required to decrease the forced expiratory volume in 1 second by 20%. N=62 adult patients with severe refractory asthma uncontrolled by beclomethasone (>960 µg/day) or equivalent were randomized 1:1 to imatinib (200 mg QD for 2 weeks then 400 mg QD thereafter) or placebo for 24 weeks. The primary endpoint was change in airway hyperresponsiveness, assessed as methacholine reactivity (PC20), from baseline to 3 and 6 months. Cahill KN, et al. N Engl J Med. 2017;376(20):1911-1920.

CHALLENGES SURROUNDING BIOLOGIC THERAPIES

Timing of Initiation, Predictors of Response, & Individualized Selection

Michael E. Wechsler, MD, MMSc

State of OCS Use in Severe Asthma

Results From a 14-year Population-Based Study

8.2%

Number of follow-up periods associated with maintenance OCS use1

Results from the International Severe Asthma Registry . . .

Number of follow-up periods associated with ≥1 episode of OCS use1

At least 30% of SA patients with high OCS exposure do not receive a biologic2

75% Patients with SA continue to have substantial exposure to OCS as episodes of increased respiratory symptoms are ubiquitously managed with courses of OCS.3

OCS-Related Toxicities in Asthma

Infections

Weight gain

Fractures

• OCS-related risk increases in a dose-dependent manner4

• Evidence suggest that T2

biomarker low asthma

symptoms do not benefit from OCS5

What Can Be Done Differently to Reduce OCS Exposure?

As little as 1 course of OCS/year on top of background high-dose ICS results in a statistically significant increase in OCS -induced morbidity.5

CHRONICLE Study in SA

Ongoing Real-World Observational Study

Interim Report (Genofre, February 2021)1

• N=959 patients with confirmed SA analyzed

–

59% had an exacerbation while not receiving biologics

–

Of these, 41% subsequently initiated biologic therapy

– The median number of days between last exacerbation and biologic initiation was 70 days for patients with 1 exacerbation vs 36.5 days for patients with ≥1 exacerbation (P<0.05)

Interim Report (Chipps, February 2022)2

• N=908 patients with confirmed SA, biologic use for ≥12 months analyzed

–

68% had no OCS use within the most recent 12 months

–

35% had majority of monthly ACT scores ≥20 and patient- and specialist-reported asthma control

Expediting access to biologic therapy for patients with uncontrolled SA should be explored.

ICS Dose Response Curve

Efficacy and Adverse Effects

Relationship of Fluticasone Propionate dose, clinical effect, and risk of systemic side effects

200-250 μg of FP or equivalent is the dose at which 80–90% of the maximum achievable therapeutic benefit is obtained in adult asthma across the spectrum of severity

Results From an Online Survey

Premeeting Clinician Poll

Which of the following challenges do you commonly experience when using biologic therapies to treat severe asthma?

Insufficient efficacy

Adverse reactions

Polypharmacy and comorbid disease

Switching biologics

Biomarkers

Patient reluctance

Selection of initial biologic

Insurance denial/access barriers

• 24% Allergy/Immunology

• 42% Family or Internal Medicine

• 33% Pulmonology

DISPARITIES IN BIOLOGIC UTILIZATION

Considerations for Overcoming Barriers to Asthma Care

The State of Biologic Use in Severe Asthma

1M patients have severe asthma in the US1

40% (400K) have been seen by a specialist2

65% (260K) are prescribed a biologic3

35% (140K) are not on a biologic despite uncontrolled SA or chronic OCS use3

60% (600K) are assumed to be managed by primary care

1. American Lung Association. Severe Asthma. Available at https://www.lung.org/lung-health-diseases/lung-disease-lookup/asthma/learn-about-asthma/types/severeasthma#:~:text=Of%20the%20more%20than%2025,by%20the%20frequency%20of%20symptoms. Accessed January 23, 2023; 2. Most JF, et al. J Allergy Clin Immunol Pract. 2021;9(10):3662-3671; 3. Panettieri RA Jr, et al. Ann Allergy Asthma Immunol. 2022;129(4):467−474; 4. Mayo Clinic. Big data helps in understanding asthma biologic use, outcomes. Available at https://advancingthescience.mayo.edu/2022/01/06/bigdata-helps-in-understanding-asthma-biologic-use-outcomes/. Accessed May 16, 2023.

Almost all of asthma biologics prescribed in the US are prescribed by specialists, and those specialists are more accessible to certain groups of people than others.4

Disparities in Biologic Use in the US

Patients with the highest rate of receiving biologic therapy1:

White, adult females

Annual income of >$75,000

Managed by specialist

Patients with highest rate of asthma mortality and ED visits due to asthma2:

Black, adult females Black, Hispanic, and Indigenous individuals in the US face the highest burden of asthma compared with White Americans.

between the number of

receiving

ED, emergency department. 1. Inselman JW, et al. J Allergy Clin Immunol Pract. 2020;8(2):549-554.e1; 2. AAFA. Asthma Disparities in America. Available at https://aafa.org/asthma-allergy-research/ourresearch/asthma-disparities-burden-on-minorities/#:~:text=The%20burden%20of%20asthma%20in,asthma%20rates%2C%20deaths%20and%20hospitalizations. Accessed January 1, 2023; 3. Burchard EG, Borrell LN. N Engl J Med. 2021; 385(24):2297-2298; 4. Mayo Clinic. Big data helps in understanding asthma biologic use, outcomes. . Available at https://advancingthescience.mayo.edu/2022/01/06/big-data-helps-inunderstanding-asthma-biologic-use-outcomes/. Accessed May 16, 2023.

Although biologic therapies represent a new dawn in medical care, the benefits are not accessible to all patients.3 There is a clear gap

people

biologics and those who would benefit from these therapies.4

Factors Contributing to Disparities in Biologic Use

Race and Ethnicity1

Biological Behavioral Sociocultural Environmental

Genetics

Nutrition Smoking

Microbiome

Diet

Education

Socioeconomic Status

Health Insurance

Health Literacy

Therapy Adherence

Psychosocial Stressors

Environmental and Health System

• Severe and poorly controlled asthma disproportionately affects the Black population2

– Asthma mortality is 4x as high among Puerto Ricans and Black Americans as among White Americans

Housing

Neighborhood

Quality of Indoor Air

Outdoor Air/Pollution

Access to Health Care

Access to Quality Foods

• Black and Hispanic populations represent only 5% and <1% of clinical trial participants, respectfully2

Health disparities, including access to biologics, are multifactorial.

The lack of racial and ethnic diversity limits the generalizability of trial results.2

Conclusions

• 6 biologic therapies are available for the treatment of severe asthma

• Despite revolutionizing the treatment of severe asthma, unmet needs and health care disparities persist with respect to biologic agent utilization

• Current challenges include:

–

Initial biologic selection, monitoring, switching, and access

• As precision medicine continues to evolve, we look ahead to: – Explore newer treatment targets

– Define biomarker thresholds and refine treatment eligibility

– Investigate outcomes in broader, underserved patient populations